British Pat. No. 1,306,517 discloses a process for converting chloropyridines to fluoropyridines by reaction with alkali metal fluorides in polar, aprotic solvents at temperatures of from 160.degree. to 250.degree. C. The solvent may or may not be mixed with water and the reaction is carried out in the presence of an acid, base or organic hydroxy compound as an "initiator". The preferred solvent is sulfolane (tetramethylene sulfone) and the preferred initiator is ethylene glycol.
In the sole example in the patent of 2,6-difluoropyridine preparation, a 62% conversion of 2,6-dichloropyridine to the difluoro derivative is reported as having been obtained by refluxing a mixture of about 2 moles of the dichloropyridine and about 8 moles of anhydrous KF in sulfolane (containing 1.2 weight percent of ethylene glycol) for 2 hours at 225.degree.-235.degree. C.
Reaction temperatures as high as 225.degree. and are not particularly attractive for 2,6-difluoropyridine production. The boiling point of the latter compound is only about 125.degree. at sea level and it is therefore necessary either to operate under a pressure at least equal to the (quite substantial) antogenous pressure of the reaction mixture or to allow the difluoro compound to distil out of the reaction mixture as formed and to provide for reflux return to avoid losses of the chloro/fluoro intermediate, which is also quite volatile. However, substantially lower reaction rates can be anticipated at lower temperatures. In fact, a reaction period of 25-30 hours is required to attain an 80% yield of the difluoropyridine at 150.degree., in DMSO, and much longer periods are required in other solvents, including sulfolane, at this temperature.
The use of DMSO as the reaction medium at higher temperatures is contraindicated by two considerations: (1) the solubility of KF in this solvent goes down, rather than up, as the temperature increases (see Table 1); and (2) DMSO is known (Traynelis et al., J. Org. Chem., 29, 221 (1964) ) to slowly decompose at reflux temperature (.about.189.degree. C.) and (according to Finger and Starr, J.A.C.S., 81, 2674 (1959) ) to react with halogen compounds. Substantial alteration of DMSO would then be expected at elevated temperatures in the presence of such inherently reactive compounds as 2,6-difluoro- or 2-chloro-6-fluoropyridine.
On the other hand, if the reaction period could be sufficiently shortened by use of an appropriate catalyst, an unacceptable degree of solvent decompositioned might not result. According to the British Pat. No. 1,306,517 patent, ethylene glycol is the "initiator" of choice. Therefore, despite the fact that ethylene glycol is known (Traynelis at al., loc. cit.) to promote alteration of DMSO, an attempt has been made to employ the glycol as a catalyst for the reaction of 2,6-dichloropyridine with KF in DMSO at 186.degree. C. 74.35 and 13.3% yields, respectively, of the difluoro and chloro/fluoro products were attained in a reaction period of 5.5 hours. However, a total of about 11% of the dichloropyridine was found to have been converted to undesired, solvent-derived byproducts. Accordingly, the use of such catalysts as ethylene glycol appears to be ruled out.
It is known that replacement of chloro substituents on aromatic rings by fluorine can be achieved at less elevated temperatures if the ring is also substituted with an activating group. Thus, Finger and Kruse reported (J.A.C.S., 78, 6034 (1956) ) that a 47% yield of a monofluoro derivative was obtained by reacting 2,4-dichloronitrobenzene with excess KF in DMSO (dimethyl sulfoxide) at 180.degree. for 6 hours; they attributed this result to activation by the nitro group. Similarly, U.S. Pat. No. 3,629,424 discloses (Example 5) that 30 grams (a 34.7% yield) of 3,5-dichloro-2,6-difluoro-4-cyanopyridine was obtained by reacting 100 grams of tetrachloro-4-cyanopyridine in DMSO at 40.degree.-50.degree. for 5 hours. However, no way of introducing a subsequently removable activating group in 2,6-dichlorpyridine is evident.
It is evident that it would be highly desirable if a method could be found whereby the reaction of KF and chlorine substituents alpha to the ring nitrogen, in pyridine compounds lacking activating substituents, could be made to proceed at more practical rates at temperatures at which solvents such as DMSO are stable to 2,6-difluoro- and 2-chloro-6-fluoropyridine. In other words, a more effective catalyst for the reaction than the "initiators" disclosed in the British Pat. No. 1,306,517 patent is needed.
Certain so-called "crown ethers" have been reported to solubilize potassium fluoride in organic solvents, by solvating the K.sup.+ ion, the F.sup.- ion accompanying the solvated cation as a closely associated counter ion. However, it has been found that crown ethers are of little value as catalysts for the fluoride/chloride exchange reaction at point.
Since the solubility of KF is generally low, the exchange reaction is essentially a heterophase reaction and a technique of catalysis appropriate to such reactions is indicated. In recent years, so-called "phase-transfer" catalysis has proven to be an effective technique for facilitating a variety of heterophase reactions. According to a cursory review of this type of catalysis included in Eastman Organic Chemical Bulletin, Vol. 48, No. 1, 1976, quaternary ammonium (and phosphonium) salts have been found to be excellent phase transfer catalysts.
The vast majority of applications of phase-transfer catalysis described in the literature involve transfer of reactive species between two liquid phases, one of which is usually aqueous. However, an example of transfer between a solid phase and an organic liquid phase has been disclosed. Huang and Dauerman reported (Industrial and Engineering Chemistry, Product Research and Development; Vol. 8, No. 3, Sept. 1969, pp. 227-232) the use of various amines and triphenyl phosphine as catalysts for anhydrous acetylations of certain aralkyl and alkyl chlorides with sodium acetate in the presence or absence of organic solvents.
Similarly, Wagenknecht et al. reported (Synthetic Communications, 2(4), 215-19 (1972) ) that ester formation is further facilitated if the alkyl halide is reacted with a solution or suspension of a preformed, hydrated quaternary ammonium carboxylate in a non-hydroxylic solvent (rather than with a metal carboxylate in the presence of an amine or ammonium salt). Similar results were obtained when the anion in the preformed salt was a phenolate or nitrate ion.
Tetraalkyl ammonium fluorides have been used to effect nucleophilic displacement of tosylate groups (in tosylated sugars or hydroxy acids) by fluoride, according to Birdsall, Tetrahedron Letters No. 28, pp. 2675-2678, 1971. There are not heterophase reactions and do not involve phase transfer catalysis. Furthermore, Birdsall reported formation of unsaturated (dehydrofluorinated) acid by-products in yields of from 30 to 100 percent, depending on the basicity of the solvent used, when tetrabutyl ammonium fluoride was employed as the fluoride source material.
The undesired formation of dehydrofluorinated acids experienced by Birdsall may be attributable to the strong tendency of fluoride ions to abstract protons from organic substrates in the presence of solvents such as DMSO. In view of the latter tendency and the fact the high charge density of the small fluoride ion makes it more difficult to solubilize than larger anions such as carboxyl, phenolate or nitrate, it could not be anticipated with confidence that quaternary ammonium or phosphonium chlorides would effectively catalyze the hetero-phase exchange reaction between KF and 2,6-dichloro- or 2-chloro-6-fluoropyridine.